(1) Field of the Invention
This invention generally relates to treatment of shock. More specifically, the invention is directed to the administration of adrenomedullin binding protein-1 to mammals in shock or at risk for shock.
(2) Description of the Related Art
References Cited
Elsasser T H, Kahl S, Martinez A, Montuenga L M, Pio R, Cuttitta F: Adrenomedullin binding protein in the plasma of multiple species: characterization by radioligand blotting. Endocrinol 140:4908-4911, 1999.
Shindo T, Kurihara H, Maemura K, Kurihara Y, Kuwaki T, Izumida T, Minamino N, Ju K H, Morita H, Oh-hashi Y, Kumada M, Kangawa K, Nagai R, Yazaki Y: Hypotension and resistance to lipopolysaccharide-induced shock in transgenic mice overexpressing adrenomedullin in their vasculature. Circulation 101:2309-2316, 2000.
Wichterman K A, Baue A E, Chaudry I H: Sepsis and septic shock: a review of laboratory models and a proposal. J Surg Res 29:189-201, 1980.
Wu R, Zhou M, Wand P: Adrenomedullin and adrenomedullin binding protein-1 downregulate TNF-α in macrophage cell line and rat Kupffer cells. Regul Pept 112:19-26, 2003.
Yang S, Zhou M., Chaudry I H: Novel approach to prevent the transition from the hyperdynamic phase to the hypodynamic phase of sepsis: Role of adrenomedullin and adrendomedullin binding protein-1. Ann Surg 236:625-633, 2002a.
Yang S, Zhou M, Gowler D E, Wang P: Mechanisms of the beneficial effect of adrenomedullin and adrenomedullin-binding protein-1 in sepsis: down-regulation of proinflammatory cytokines. Crit Care Med 30:2729-2735, 2002b.
Shock, or circulatory insufficiency leading to inadequate blood flow to vital organs, is a potentially life-threatening medical emergency that often leads to organ damage, cardiac arrest, respiratory failure and death.
Shock can be caused by heart problems (cardiogenic shock), conditions blocking blood flow to or from the heart (extracardiac obstructive shock), loss of fluids (hypovolemic shock), or abnormal flow of fluids into the tissues (distributive shock). These dysfunctions in circulation can in turn be caused by bacterial blood infection (septic shock), severe allergic reaction (anaphylaxis), trauma (traumatic shock), severe bleeding (hemorrhagic shock), or neurologic dysfunction causing abnormal opening of blood vessels (neurogenic shock). While any shock is serious, septic shock and hypovolemic shock are particularly important due to their frequency of occurrence and frequently inadequate treatment regimens.
Despite attempts to improve survival of septic patients with intensive medical care, including antibiotics, aggressive intravenous fluids, nutrition, mechanical ventilation, and surgical interventions, the mortality rate still ranges from 30% to 50%. Of clinical trials testing novel agents for the treatment of sepsis, only activated protein C has previously been demonstrated to significantly reduce mortality in patients with severe sepsis. The high morbidity and mortality attributed to sepsis could be due to the fact that mediators or factors responsible for the transition from the hyperdynamic phase to the hypodynamic phase of sepsis are not fully understood. Consequently, there is a progressive deterioration of cell and organ functions and even death of the host, which might be prevented by interventions directed against and/or modulating these mediators/factors. It is therefore important to investigate the subtle alterations in cellular function and mechanisms of pathophysiological changes during sepsis and develop novel therapeutic strategies. In this regard, experimental polymicrobial sepsis induced by cecal ligation and puncture (CLP) mimics many features of clinical sepsis-peritonitis and is associated with an early, hyperdynamic phase (characterized by increased cardiac output and tissue perfusion, decreased vascular resistance, hyperglycemia and hyperinsulinemia) followed by a late, hypodynamic phase (characterized by reduced cardiac output and tissue perfusion, increased vascular resistance, hypoglycemia and hypoinsulinemia). The CLP model of sepsis has been used extensively to study the pathophysiologic and immunologic alterations in sepsis.
Despite advances in the trauma management, a large number of patients with traumatic injury die of hypovolemic circulatory collapse due to severe hemorrhage. Irreversible circulatory shock induced by traumatic injury and blood loss represent a major clinical problem, particularly in combat casualties. Traumatic injury (often accompanied by severe blood loss) is the principal cause of death in patients aged 1-44 years and the overall leading cause of life-years lost in the United States. Traumatic injury accounts for 37 million emergency department visits, 2.6 million hospital admissions, and 150,000 deaths each year. The resulting loss of productive life years exceeds that of any other disease, with societal costs of $260 billion annually. In less than two decades, trauma will equal to or surpass communicable diseases as the leading worldwide cause of disability-adjusted life-years lost. Although more effective prevention measures will reduce the early deaths resulting from massive hemorrhage and central nervous system injury, the transition from the reversible to the irreversible hypovolemia, or circulatory collapse, appears to be responsible for the majority of late deaths after trauma and blood loss.
Shock generally progresses in four stages. The initial stage is characterized by cardiac output insufficient to meet the body's metabolic needs, but not otherwise low enough to produce significant symptoms. The patient is anxious and alert, with altered mental status, and increased respirations. In the second, or compensatory, stage the patient exhibits an increase in heart rate, an increase in cardiac output, and vasoconstriction. The third, or progressive, stage of shock is characterized by falling blood pressure, increased heart rate, oligoria, and increasing system dysfunction. In the fourth, or irreversible stage, death is inevitable. The patient in the irreversible stage exhibits myocardial depression and massive capillary dilation, with blood pooling in the extremities.
Adrenomedullin, a newly reported and potent vasodilatory peptide, is an important mediator involved in both physiological and pathological states. Human AM, a 52-amino acid peptide, was first isolated and reported in 1993. AM has a carboxy terminal amidated residue and a 6-member ring structure formed by an intramolecular disulfide bond near the amino terminus, and is available commercially. Rat adrenomedullin has 50 amino acids with 2 amino acid deletions and 6 substitutions as compared to human adrenomedullin. Adrenomedullin transcripts and protein are expressed in a large number of tissues, and circulating levels of adrenomedullin were observed under normal as well as pathophysiological conditions. Previous studies using the CLP model of sepsis have shown that up-regulation of adrenomedullin plays a major role in initiating the hyperdynamic response during the early stage of sepsis, and reduced vascular responsiveness to adrenomedullin appears to be responsible for the transition from the hyperdynamic phase to the hypodynamic phase during the progression of polymicrobial sepsis.
In 1999, Elsasser et al. reported that specific adrenomedullin binding proteins (AMBP) exist in the plasma of several species including humans. More recently, the binding protein AMBP-1 has been identified in human plasma and has been shown to be identical to human complement factor H. AMBP-1 enhances adrenomedullin-mediated induction of cAMP in fibroblasts, augments the adrenomedullin-mediated growth of a cancer cell line, and suppresses the bactericidal capability of adrenomedullin on E. coli. 
Studies by Shindo et al. (2000) have shown that a chronic increase in vascular adrenomedullin production in transgenic mice is protective against circulatory collapse, organ damage, and mortality of endotoxic shock. It was previously unknown whether adrenomedullin+AMBP-1 down-regulates proinflammatory cytokines and, if so, whether the beneficial effects of adrenomedullin+AMBP-1 are due to this down-regulation.
It has been previously demonstrated that proinflammatory cytokines play a critical role in the initiation and progression of sepsis syndrome and that TNF-α, IL-1β and IL-6 are important mediators of hemodynamic, metabolic and immunologic alterations in the host during sepsis. Studies have also shown that circulating levels of TNF-α, IL-1β and IL-6 increase significantly in the early, hyperdynamic phase of sepsis and remain elevated in the late, hypodynamic phase of sepsis. Although adrenomedullin is up-regulated following stimulation with TNF-α and IL-1β, some studies have shown that adrenomedullin suppresses IL-1β-induced TNF-α production in vivo and suppresses the secretion of TNF-α and IL-6 from RAW 264.7 cells stimulated with endotoxin in vitro.